Immunologically mediated diseases such as asthma, allergies, and autoimmunity are important causes of morbidity. Naturally occurring regulatory T cells (NatTregs) show significant promise as potential tools/targets for immunomodulatory therapies. NatTregs require interleukin (IL) 2 and T cell receptor (TCR) activation to gain maximal suppressive ability. Regulatory T cells can be induced (IndTregs) de novo from T helper (Th)cells by activation in the presence of TGFp. However, little is known about the influence of pro- inflammatory cytokines on Treg function and phenotype. Recent studies including our own suggest an important regulatory role for the proximally induced pro-inflammatory cytokine, IL-6, and the cytokines critical for the adaptive immune response, IL-4and IFN-y, in the development and function of NatTregs and/or IndTregs. The central hypothesis that will be developed in this proposal is that the generation and function of Tregs are influenced by specific cytokines. This has important ramifications in use of Tregs in therapy. To test this hypothesis, we will: Aim 1: Investigate the effect of IL-6on FoxPS expression and suppressive function in NatTregs. Aim 2: Characterize modulation of IndTregs by cytokines during and after induction. A model of Aspergillus hypersensitivity will be used to investigate IndTreg function in vivo.